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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/18—Sulfonamides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/426—1,3-Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to a CXCL8 inhibitor, such as reparixin or ladarixin, and a pharmaceutical composition thereof for use in the prevention or treatment of cancer- related fatigue, said fatigue being either related to cancer or to an anti-tumoral treatment, such as chemotherapy, radiotherapy or biological therapy.
• a CXCL8 inhibitor such as reparixin or ladarixin
• a pharmaceutical composition thereof for use in the prevention or treatment of cancer- related fatigue, said fatigue being either related to cancer or to an anti-tumoral treatment, such as chemotherapy, radiotherapy or biological therapy.
• Cancer-related fatigue is one of the most common symptoms experienced by cancer patients, occurring in more than 60% of cancer patients and more than 80% of those receiving cancer treatment. Cancer-related fatigue is reported to be the single most distressing symptom with the greatest negative impact on quality of life. It starts before diagnosis and persists for months or years after treatment completion.
• Cancer treatments such as chemotherapy, radiation therapy or radiotherapy, and biologic therapy can cause or worsen fatigue in cancer patients. Fatigue is also a common symptom of some types of cancer.
• CCF cancer-related fatigue
• the terms “asthenia” and “weakness” were used to describe a subjective sensation of tiredness, while the specific term “fatigue” was used to describe a symptom of tiredness precipitated by effort.
• the term “fatigue” was used to refer to weariness or exhaustion resulting from physical or mental exertion, while “asthenia” was used to refer to weariness or exhaustion without physical or mental exertion.
• fatigue has gained a more widespread acceptance in the medical literature and is preferentially used in the National Cancer Institute toxicity grading scale that covers generalized weakness.
• health professionals may use terms such as asthenia, lassitude, prostration, lack of energy and weakness.
• Patients describe fatigue as feeling tired, weak, worn-out, heavy, slow, or that they have no energy or get-up-and-go.
• ICD-10 International Classification of Diseases
• This has been set to define the fatigue syndrome in all stages of cancer, from ongoing treatment to advanced stages of the disease as well as to survivorship.
• the term “fatigue” is used to include all the above terms and symptoms related to cancer or cancer treatment. Clinicians, patients, family members, and researchers are increasingly recognizing that CRF represents a significant consequence of cancer and its treatment and requires clinical attention and intervention. Fatigue is one of the most frequently anticipated adverse effects of cancer treatment: 95% of patients who are scheduled to receive chemotherapy, radiotherapy or biological therapy expect to experience some degree of fatigue during their treatment. Reported incidence rates for CRF in the clinical trial setting tend to be in the range of 70%-80%. (M. Flofman et al, The Oncologist, 2007, vol. 12, pages 4-10). Evidence-based treatments for CRF are scarce.
• the applicant has identified a new treatment able to effectively control cancer-related fatigue.
• a CXCL8 inhibitor such as reparixin or ladarixin
• the applicant has found that in a multicentre, double-blind placebo-controlled clinical trial aimed to evaluate the progression-free survival of cancer patients treated by paclitaxel with and without the addition of reparixin, there was a significantly lower incidence and severity of treatment-related fatigue in the group of subjects treated with paclitaxel plus reparixin compared with the group of subjects treated with paclitaxel and placebo. Moreover, the applicant has also found that in a prospective pilot study the addition of ladarixin to doxorubicin and oclacitinib reduced the severity of the known fatigue associated to the treatment.
• the present invention relates to a CXCL8 inhibitor for use in the prevention or treatment of cancer-related fatigue in a cancer patient, more in particular of cancer-related-fatigue caused by an anti-tumoral treatment, preferably chemotherapy, radiotherapy or biological therapy.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a CXCL8 inhibitor and at least one inert pharmaceutically acceptable excipient, for use in the prevention or treatment of cancer-related fatigue, more in particular of cancer-related fatigue caused by an anti-tumoral treatment, preferably chemotherapy, radiotherapy or biological therapy.
• the present invention relates to a method of preventing or treating cancer-related fatigue in a cancer patient, comprising administering to the subject a CXCL8 inhibitor.
• a first aspect of the present invention relates to a CXCL8 inhibitor for use in the prevention or treatment of cancer-related fatigue in a cancer patient.
• said patient is undergoing an anti-tumoral treatment, preferably chemotherapy, radiotherapy or biological therapy, more preferably chemotherapy.
• an anti-tumoral treatment preferably chemotherapy, radiotherapy or biological therapy, more preferably chemotherapy.
• said cancer-related fatigue is caused or worsened by said anti-tumoral treatment practiced on the patient, preferably chemotherapy, radiotherapy or biological therapy, more preferably chemotherapy.
• CXCL8-inhibitor refers to any compound able to inhibit, partially or totally, the biological activity of CXCL8. Such a compound can act by decreasing the expression of CXCL8 or of its receptor(s) or by inhibiting the triggering of the intracellular signaling activated by the CXCL8 receptor(s). It is preferred that said CXCL8 activity inhibitor is able to inhibit at least 60%, preferably at least 70%, more preferably at least 80%, even more preferably at least 90% of PM Ns chemotaxis induced by an optimal concentration of CXCL8 (1 nM) at a concentration equal or below 500 nM, preferably below 100 nM.
• the CXCL8 inhibitor according to the present invention inhibits the activity of CXCL8 mediated by CXCR1 receptor or mediated by both CXCR1 and CXCR2 receptors.
• said CXCL8 inhibitor is a CXCL8 receptor(s) inhibitor, which inhibits binding of CXCL8 to its receptor(s) or the intracellular signaling activated by the binding of CXCL8 to its receptor(s).
• said CXCL8 receptor inhibitor is either an allosteric inhibitor or an orthosteric antagonist of CXCR1 receptor or of both CXCR1 and CXCR2 receptors.
• the CXCL8 receptor(s) inhibitor according to the invention has an IC50 value towards CXCR1 receptor in the low nanomolar range, preferably in the range 0.02- 5 nanomolar.
• said CXCL8 inhibitor is selected from small molecular weight molecules, peptides and antibodies, more preferably it is a small molecular weight molecule.
• CXCL8 inhibitors according to the above definition, able to inhibit the activity of CXCL8 mediated by CXCR1 receptor or mediated by both CXCR1 and CXCR2 receptors, are well known in the art.
• CXCL8 inhibitors such as small molecules, peptides and antibodies
• CXCL8 inhibitors have been disclosed, many of which are currently under undergoing clinical trials or are used in therapy.
• Chao J. et al. Bioorganic & Medicinal Chemistry Letters 17, 2007, p. 3778-3783
• CXCL8 inhibitors according to the present invention are disclosed in W02000/024710A1 and W02005/090295, that also disclose their method of synthesis, their activity as CXCL8 inhibitors as well as their use as inhibitors of neutrophils chemotaxis and degranulation induced by CXCL8 and in the treatment of CXCL8 dependent pathologies.
• CXCL8 inhibitors particularly preferred in the present invention are those of the following formula (I): wherein
• R 1 is selected from a linear or branched C1-C6 alkyl, benzoyl, phenoxy, and trifluoromethanesulfonyloxy;
• R 2 is selected from hydrogen atom and linear or branched C1 -C3 alkyl; and R 3 is a linear or branched C1-C6 alkyl or trifluoromethyl, or a pharmaceutically acceptable salt thereof.
• R 1 is selected from benzoyl, isobutyl, and trifluoromethanesulfonyloxy. More in particular, R 1 is preferably linked to the phenyl ring in 3- or 4-position. According to the most preferred embodiment, R 1 is 3-benzoyl, 4-isobutyl or 4-trifluoromethanesulfonyloxy.
• R 2 is selected from hydrogen atom or methyl.
• R 3 is selected from linear or branched C1-C6 alkyl, more preferably from linear of branched C1 -C3 alkyl. According to the most preferred embodiment, R 3 is methyl.
• the chiral carbon of the compounds of formula (I) is in the RS or R configuration, more preferably it is in the R configuration.
• CXCL8 inhibitors of formula (I) are:
• CXCL8 inhibitors are those disclosed in WO2010/031835, that also disclose their method of synthesis, their activity as CXCL8 inhibitors as well as their use as inhibitors of neutrophils chemotaxis and degranulation induced by CXCL8 and in the treatment of CXCL8 dependent pathologies.
• CXCL8 inhibitors particularly preferred in the present invention are those of the following formula (II): and pharmaceutically acceptable salts thereof, wherein:
• R1 is hydrogen
• X is OH
• R2 is hydrogen or linear C1-C4 alkyl
• Y is a heteroatom selected from S, O and N,
• Z is selected from linear or branched C1 -C4 alkyl, linear or branched C1 -C4 alkoxy, halo C1 -C3 alkyl and halo C1 -C3 alkoxy.
• the chiral carbon of the compounds of formula (II) is in the is in the RS or S configuration, more preferably in the S configuration.
• CXCL8 inhibitors of formula (II) is 2-(4- ⁇ [4- (trifluoromethyl)-l ,3-thiazol-2-yl]amino ⁇ phenyl)propanoic acid, preferably (2S)-2-(4- ⁇ [4- (trifluoromethyl)-l ,3-thiazol-2-yl] amino ⁇ phenyl) propanoic acid or the sodium salt thereof (also known as DF2755A).
• CXCL8 inhibitors are R-(-)-2-(4- isobutylphenyl)propionyl methansulfonamide and pharmaceutically acceptable salts thereof, preferably the lysine in situ salt thereof, and R(-)-2-(4- trifluoromethanesulfonyloxy)phenyl]-N-methanesulfonyl propionamide and pharmaceutically acceptable salts thereof, preferably the sodium salt thereof.
• the CXCL8 inhibitor compounds of the present invention may form stable pharmaceutically acceptable acid or base salts with a pharmaceutically acceptable organic or inorganic acid or base, and in such cases administration of a compound as a salt may be appropriate.
• acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate,
• base addition salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N- methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine, and so forth.
• basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and others.
• Non toxic physiologically-acceptable salts are preferred, although other salts may be useful, such as in isolating or purifying the product.
• the salts may be formed by conventional means, such as by reacting the free form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble, such as for example water or ethanol, which is removed under vacuum or by freeze drying.
• the present invention also includes the prodrugs, stereoisomers, isotope-labelled, for example deuterated, derivatives and enantiomers of the CXCL8 inhibitor compounds described above.
• prodrug refers to an agent, which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form).
• Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
• the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
• prodrug a compound of the present invention wherein it is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolysed once inside the cell where water solubility is beneficial.
• Prodrugs have many useful properties. For example, a prodrug may be more water- soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A prodrug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
• Ester prodrugs of the CXCL8 inhibitor compounds disclosed herein are specifically contemplated. While not intending to be limiting, an ester may be an alkyl ester, an aryl ester, or a heteroaryl ester.
• alkyl has the meaning generally understood by those skilled in the art and refers to linear, branched, or cyclic alkyl moieties.
• Ci_e alkyl esters are particularly useful, where alkyl part of the ester has from 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and combinations thereof having from 1 to 6 carbon atoms.
• CXCL8 inhibitor compounds may exist in tautomeric forms, and this invention includes all such tautomeric forms of those compounds unless otherwise specified.
• structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric centre.
• single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
• this invention encompasses each diastereomer or enantiomer substantially free of other isomers (>90%, and preferably >95%, free from other stereoisomers on a molar basis) as well as a mixture of such isomers.
• optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereomeric salts, by treatment with an optically active acid or base.
• appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereomers by crystallization followed by liberation of the optically active bases from these salts.
• a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
• Still another method involves synthesis of covalent diastereomers by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
• the synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolysed to deliver the enantiomerically pure compound.
• Optically active compounds of the invention can be obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
• chemotherapy refers to any cancer treatment using an antitumor chemotherapeutic agent (including but not limited to alkylating agents, anthracyclines, cytoskeletal disruptors (taxanes), antimetabolites, topoisomerase I and II inhibitors, kinase inhibitors, platinum-based agents, and vinca alkaloids) to kill cancer cells and reduce or eliminate the growth or proliferation of tumors.
• an antitumor chemotherapeutic agent including but not limited to alkylating agents, anthracyclines, cytoskeletal disruptors (taxanes), antimetabolites, topoisomerase I and II inhibitors, kinase inhibitors, platinum-based agents, and vinca alkaloids
• antigenitumor chemotherapeutic agent refers to any compound employed in the cancer therapy able to kill the cancer cells, such as for example, alkylating agents, anthracyclines, cytoskeletal disruptors (taxanes), antimetabolites, topoisomerase I and II inhibitors, kinase inhibitors, platinum-based agents, vinca alkaloids, and the like.
• Chemotherapeutic agents are known in the art. A non-exhaustive compilation can be easily found at https://en.wikipedia.org/wiki/List_of_antineoplastic_agents.
• chemotherapeutic agents are (i) alkylating agents, such as, for example, cyclophosphamide, mechlorethamine, chlorambucil, melphalan, (ii) anthracyclines, such as for example, doxorubicin, epirubicin, mitoxantrone, pixantrone, losoxantrone, and daunorubicin, (iii) cytoskeletal disruptors (taxanes), such as, for example, paclitaxel, docetaxel, abraxane, and taxotere, (iv) antimetabolites, such as, for example, azacitidine, azathioprine, capecitabine, cladribine, cytarabine, doxifluridine, hydroxyurea, methotrexate; 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, pemetrexed, 5-fluorouracil
• radiotherapy refers to any cancer treatment using a source of high-energy radiation, including but not limited to X-rays, gamma rays, particle beams, proton beam therapy, and high-energy photon radiation, to kill cancer cells and reduce or eliminate the growth or proliferation of tumors, such as for example external radiation therapy (such as e.g., intraoperative radiotherapy and prophylactic cranial irradiation (PC), intensity-modulated radiation therapy (IMRT), stereotactic (or stereotaxic) radiosurgery, three-dimensional (3-D) conformal radiation therapy, Volumetric modulated arc therapy (VMAT), particle therapy, Auger therapy), internal radiation therapy (such as e.g., interstitial radiation therapy, intracavitary or intraluminal radiation therapy), and systemic radiation therapy (such as e.g., Iodine-131 ( 131 l), Radium-223 ( 223 Ra), Strontium-89 ( 89 Sr), Phosphorus-32 ( 32 Phosphorus-32 ( 32 Phos
• biological therapy refers to a treatment of cancer that uses the immune system of the patient to kill the cancer cells, by targeting the cancer cells directly, for example through antibodies, or indirectly by inducing the immune system to attack the cancer cells or by making cancer cells easier for your immune system to recognize.
• a preferred biological therapy according to the invention is immunotherapy.
• the CXCL8 inhibitor is for use in cancer-related fatigue caused or worsened by treatment with a chemotherapeutic agent.
• a chemotherapeutic agent is selected from cisplatin, paclitaxel, docetaxel, abraxane, taxotere, 5-fluorouracil, more preferably it is paclitaxel.
• the CXCL8 inhibitor for use according to the first aspect of the invention is administered in the form of a pharmaceutical composition.
• a second aspect of the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a CXCL8 inhibitor and at least one inert pharmaceutically acceptable excipient, for use in the prevention or treatment of cancer-related fatigue, more in particular of cancer-related fatigue caused by an anti-tumoral treatment, such as chemotherapy or radiotherapy, as above defined.
• the pharmaceutical composition of the present invention is prepared in suitable dosage forms comprising an effective amount of a CXCL8 inhibitor, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof, and at least one inert pharmaceutically acceptable excipient.
• the administration of the pharmaceutical composition of the present invention to a patient is in accord with known methods and may comprise from one to several oral administrations per day (for example, two times a day (BID) or four times a day (QID)), parenteral administration (including intravenous, intraperitoneal, intracerebral, intrathecal, intracranial, intramuscular, intraarticular, intrasynovial, intrasternal, intraocular, intraarterial, subcutaneous, intracutaneous or intralesional injection or infusion techniques), topical, buccal and suppository administration, or by sustained release systems among other routes of administration.
• parenteral administration including intravenous, intraperitoneal, intracerebral, intrathecal, intracranial, intramuscular, intraarticular, intrasynovial, intrasternal, intraocular, intraarterial, subcutaneous, intracutaneous or intralesional injection or infusion techniques
• topical buccal and suppository administration, or by sustained release systems among other routes of administration.
• the wording "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response).
• the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically- acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
• the pharmaceutical composition of the present invention comprises a CXCL8 inhibitor together with a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, diluents, or other vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• a pharmaceutically acceptable excipient includes any and all solvents, diluents, or other vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• materials which can serve as pharmaceutically acceptable excipient include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; sterilized water; Ringer's solution; buffered saline; dextrose solution; maltodextrin
• composition of the present invention may be suitably formulated using appropriate methods known in the art or by the method disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton Pa.
• pharmaceutically acceptable and “physiologically acceptable” are intended to define, without any particular limitation, any material suitable for preparing a pharmaceutical composition to be administered to a living being.
• the dosage forms can also contain other traditional ingredients such as: preservatives, stabilizers, surfactants, buffers, salts for regulating osmotic pressure, emulsifiers, sweeteners, colorants, flavourings and the like. Also specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including for example the activity and half life of the specific compound employed, the age, body weight, general health status, sex, diet, severity and course of the disease.
• the amount of a CXCL8 inhibitor or the pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention can vary over a wide range depending on known factors, for example, the molecule used, the severity of the disease, the patient's body weight, the dosage form, the chosen route of administration, and the number of administrations per day. However, a person skilled in the art can determine the optimum amount in easily and routinely manner.
• the amount of said CXCL8 inhibitor or the pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention will be such as to ensure a dosage per single administration of from 400 to 1400 mg, preferably from to 800-1200 mg, even more preferably 1200 mg, to be administered three times a day.
• the dosage forms of the pharmaceutical composition of the present invention can be prepared by techniques that are familiar to a pharmaceutical chemist, and comprise mixing, granulation, compression, dissolution, sterilization and the like.
• the present invention relates to a method of treating cancer-related fatigue in a cancer patient, comprising administering to the patient a CXCL8 inhibitor as above defined.
• the above method preferably comprises the steps of i) identifying a cancer patient suffering from cancer-related fatigue, and ii) administering to said patient a composition comprising a CXCL8 inhibitor, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof.
• said patient is undergoing an anti-tumoral treatment, preferably chemotherapy, radiotherapy or biological therapy.
• said cancer related fatigue is caused or worsened by said anti-tumoral treatment practiced on the patient
• said CXCL8 inhibitor is administered in form of a pharmaceutical composition, as above defined.
• the CXCL8 inhibitor is administered simultaneously or sequentially with an anti-tumoral treatment.
• the study was a two arm, phase 2 study to evaluate the efficacy of the administration of paclitaxel and reparixin compared to paclitaxel and placebo in metastatic TNBC patients.
• the study was conducted with 56 sites actively screening patients in the United States of America, Italy, France, Belgium, Spain, Czech Republic and Tru.
• the first patient was enrolled on 29 July 2015 and the last patient was enrolled on 30 July 2018.
• the data cut-off for main analysis was 20 February 2019. The trial was terminated after 123 patients were randomized.
• PFS progression-free survival
• PD progression-free survival
• RECIST Response Evaluation Criteria in Solid Tumors
• the exploratory objectives of the study were: • to determine time to new metastasis (new lesions at existing or new sites),
• CSCs cancer stem cells
• the study comprised two treatment groups:
• Group 1 paclitaxel 80 mg/m 2 intravenous (i.v.) (Days 1 , 8, and 15 of 28-day cycle) + reparixin oral tablets 1200 mg three times a day (t.i.d.) continuing from Day 1 to Day 21.
• Group 2 paclitaxel 80 mg/ m 2 i.v. (Days 1 , 8, and 15 of 28-day cycle) + placebo oral tablets 1200 mg t.i.d. continuing from Day 1 to Day 21.
• Tumor response and/or progression assessments were performed and documented every eight weeks according to RECIST criteria version 1.1. Metastatic tissue samples were analyzed for evaluation of CD24- CD44+ and aldehyde dehydrogenase positive (ALDH+) CSCs.
• Toxicity was defined according to the grading scale for each parameter. According to this scale, the presence and intensity of fatigue is defined as follows:
• Grade 3 Fatigue not relieved by rest, limiting self care ADL where instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, and the like and self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, but not bedridden.
• dogs received doxorubicin at 25 mg/kg IV, oclacitinib at 0.4-0.6 mg/kg orally twice per day (label dose) and ladarixin at 15 mg/kg twice per day.

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